Physicians' Academy for Cardiovascular Education

Initial results of CRISPR-Cas9-based therapy targeting knockout of TTR gene in ATTR amyloidosis

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

Literature - Gillmore JD, Gane E, Taubel J et al., - NEJM 2021, DOI: 10.1056/NEJMoa2107454

Introduction and methods

Transthyretin amyloidosis (ATTR amyloidosis) is characterized by accumulation of amyloid fibrils composed of misfolded transthyretin (TRR) protein. The clinical phenotype of ATTR amyloidosis consists of polyneuropathy, cardiomyopathy or heart failure and ATTR amyloidosis is associated with reduced survival.

Therapies for patients with ATTR amyloidosis are targeted at reducing amyloid formation by stabilizing TTR or by inhibition of TTR protein synthesis [1-4]. These therapies result in improved outcomes, but long-term administration is required in order to maintain TTR knockdown.

Use of the CRISPR-Cas9 system for in vivo gene editing may overcome limitations of mRNA targeting-based gene silencing. ATTR amyloidosis represents an ideal target for this therapy because it is a monogenic disease, TTR has limited and specific normal function and TTR is produced almost entirely in the liver. The CRISPR-Cas9-based therapy NTLA-2001 has been developed to edit the TTR gene in hepatocytes. Preliminary data in animal models showed large durable reductions in serum TTR protein [5,6].

This study reported interim data of an ongoing phase I, open-label, multicenter study evaluating the single increasing doses of NTLA-2001 for TTR editing and knockout in patients with hereditary ATTR amyloidosis with polyneuropathy. Patients were treated with a single dose of NTLA-2001 (RNA dose of 0.1 mg per kg of body weight or 0.3 mg per kg of body weight). Patients were monitored for assessment of adverse events and laboratory findings. Outcome of this analysis including 6 patients is TTR protein levels at baseline compared to those at day 28.

Main results


These interim data of an ongoing study evaluating administration of NTLA-2001 in patients with hATTR amyloidosis showed large reductions in serum TTR protein in six patients, with a mean 52% reduction in group that received 0.1 mg per kg and 87% reduction in the group that received 0.3 mg kg. These initial results demonstrate clinical proof of concept for in vivo CRISPR-Cas9-mediated gene editing as therapeutic strategy.


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